Obesity is a well-established risk factor for a number of diseases, including type 2 diabetes and coronary heart disease. While weight loss is the most effective treatment of type 2 diabetes, current methods for reducing weight are typically insufficient for long-term weight loss. The mission of AdipoGenix, Inc. is to discover, develop, and license novel therapeutics acting at the level of the fat cell for the treatment of obesity and related disorders. Obesity is a result of both fat cell enlargement and an increase in fat cell number. Preadipocytes are precursor cells in fat tissue capable of replicating or differentiating into fat cells. A decrease in the number of preadipocytes in fat tissue results in a decrease in body weight. We propose to develop a high-throughput primary screen to identify specific inhibitors of preadipocyte replication. Furthermore, we will devise secondary screens utilizing various cell types to characterize the cell-type specificity of active compounds identified in the primary screen. Importantly, primary cells will be used in these assays, since several other agents such as hormones and paracrine factors have been shown in the past to affect euploid primary cells and aneuploid cell lines differently. In addition, we will further characterize a unique inhibitor of rodent and human preadipocyte replication that we have identified. This heat stable, low molecular weight inhibitor is produced in an age-dependent manner from rodent preadipocytes. We will scale up production of this inhibitor and characterize its structure. Specific inhibitors identified through these efforts are expected to lead to development of novel, effective drugs for weight loss. PROPOSED COMMERCIAL APPLICATIONS: In the U.S., obesity costs the national economy more than $70 billion annually in both direct and indirect health care costs. Despite the obvious medical need, existing marketed drugs are marginally effective toward weight loss. Assays for inhibitors of preadipocyte replication will lead to the discovery of novel compounds to combat obesity specifically and that will have significant market potential.